Integrin alpha v beta 3 - a target for inhibiting tumor angiogenesis

Fri, 06/12/2015 - 14:37

Integrins are a family of transmembrane proteins involved in diverse processes including cell adhesion, signal transduction, cell migration, and differentiation. They exist as heterodimers consisting of noncovalently linked alpha and beta subunits. Integrin complexes span the plasma membrane and link the cytoskeleton with the extracellular matrix. In mammals there are 18 alpha and 8 beta subunits that can assemble into 24 distinct integrin heterodimers with alternative splicing adding even more diversity. In addition to binding the extracellular matrix, integrins also bind to endogenous ligands including soluble proteins and cell surface proteins. Integrin alpha v beta 3 (Integrin αvβ3), also known as the vitronectin receptor, has important roles in angiogenesis and tumor metastasis and binds to a wide range of extracellular matrix proteins containing the RGD-motif. Integrin alpha v beta 3 is highly expressed in cells of the bone, placenta, and invasive tumors where it regulates their growth, survival, motility, and differentiation. The interaction of integrin alpha v beta 3 with FGF-2, VEGF, and MMP-2 make it an attractive target to inhibit for targeted cancer therapies. Monoclonal integrin alpha v beta 3 antibodies such as Vitaxin and Abegrin are being developed and tested in clinical trials for the treatment of colorectal cancer. While these integrin alpha v beta 3 antibodies have been shown to successfully block some angiogenic pathways, angiogenesis is still able to proceed by other mechanisms (1). This suggests monoclonal integrin alpha v beta 3 antibodies may be of value in combination therapies. While the early generations of these targeted therapies have been mostly disappointing, new treatments consisting of integrin alpha v beta 3 antibodies that are able to bind to multiple integrin receptor complexes and therefore block angiogenesis on multiple fronts have shown promise in cell culture and xenograft models. The expression of integrin alpha v beta3 in osteoclasts and its role in bone resorption may also make monoclonal integrin alpha v beta 3 antibodies like Vitaxin potential candidates for the treatment of rheumatoid arthritis (2).